Seven transmembrane-spanning receptors (7TMRs or G protein-coupled receptors, GPCRs) represent the largest family of signal-transducing molecules known. For example, 7TMRs comprise more than 4% of the genes in Caenorhabditis elegans. 7TMRs convey signals for light and many extracellular regulatory molecules, such as, hormones, growth factors and neurotransmitters, that regulate every cell in the body. Dysregulation of 7TMRs has been found in a growing number of human diseases and 7TMRs have been estimated to be the targets of more than 30% of the drugs used in clinical medicine today. Thus, understanding how 7TMRs function at the molecular level is an important goal of biological research. We have used receptors for thyrotropin-releasing hormone (TRH) (TRH-Rs), for thyroid-stimulating hormone (TSH-R) and Free Fatty Acid Receptor 1 (GPR40) as model 7TMRs to study their structure and function. During this year, we have studied several new aspects of TRH-R and TSH-R structure and function. Using mutagenesis and molecular modeling approaches, we gained insight into how inverse agonists act in 7TMRs and how conformational changes lead to activation of 7TMRs. We identified a new series of 1-(phenyl)isoquinoline carboxamide analogs that are the first ligands that discriminate between the two subtypes of TRH-Rs, mTRH-R1 and mTRH-R2 and low molecular weight agonists and antagonists for TSH-R.